TLR3 Signaling Promotes the Induction of Unique Human BDCA-3 Dendritic Cell Populations.

Conventional and plasmacytoid dendritic cells (cDCs and pDCs) are the two populations of DCs that can be readily identified in human blood. Conventional DCs have been subdivided into CD1c(+), or blood dendritic cells antigen (BDCA) 1 and CD141(+), or BDCA-3, DCs, each having both unique gene expression profiles and functions. BDCA-3 DCs express high levels of toll-like receptor 3 and upon stimulation with Poly I:C secrete IFN-ß, CXCL10, and IL-12p70. In this article, we show that activation of human BDCA-3 DCs with Poly I:C induces the expression of activation markers (CD40, CD80, and CD86) and immunoglobulin-like transcript (ILT) 3 and 4. This Poly I:C stimulation results in four populations identifiable by flow cytometry based on their expression of ILT3 and ILT4. We focused our efforts on profiling the ILT4(-) and ILT4(+) DCs. These ILT-expressing BDCA-3 populations exhibit similar levels of activation as measured by CD40, CD80, and CD86; however, they exhibit differential cytokine secretion profiles, unique gene signatures, and vary in their ability to prime allogenic naïve T cells. Taken together, these data illustrate that within a pool of BDCA-3 DCs, there are cells poised to respond differently to a given input stimulus with unique output of immune functions.

Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis.

Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.

Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible to HIV infection.

CD4+CD25+ human regulatory T cells (Treg cells), which express the transcription factor FoxP3, suppress T cell activation. In this study, we sought to define cellular and molecular mechanisms of human Treg cell differentiation. A subset of human naive CD4+ T cells that are CD25+ express high levels of FoxP3. We show that upon activation through the TCR, these FoxP3-expressing naive T cells (termed TNreg cells) greatly expand in vitro. Expanded TNreg cells acquire a full Treg phenotype with potent suppressive activity and display low IL-2 production upon TCR stimulation. TNreg cells in which FoxP3 expression was reduced through RNA interference lost their suppressive activity, but retained their low IL-2 secretion in response to TCR stimulation. Furthermore, in support of the notion that TNreg cells represent a separate lineage of naive cells, we found that they were more susceptible to HIV infection as compared with naive CD4+ T cells. Based on these findings, we propose that TNreg cells are precursors for human Treg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function. Accordingly, modulation of TNreg cell numbers during infections such as HIV may disrupt human Treg cell development, and contribute to chronic immune activation.

Protein kinase C-theta;: signaling from the center of the T-cell synapse.

The hypothesis that protein kinase C (PKC)-theta; plays an important role in T-lymphocyte activation, as indicated by numerous studies in cell lines, was recently confirmed in mice deficient in the expression of this enzyme. In response to TCR stimulation, peripheral T cells lacking PKC-theta; failed to activate NF-kappaB and AP-1, and to express IL-2. This revealed a critical function for this PKC family member in linking membrane-proximal activation cascades to transcriptional responses governing T-cell activation. Although the molecular interactions in which PKC-theta; engages have not been fully delineated, insights from a variety of recent studies have permitted new models to be formulated regarding the mechanisms through which it achieves its unique effector functions.